P497: PROGNOSTIC IMPACT OF RAS AND C-KIT MUTATIONS (SINGLE VS. MULTIPLE) IN CORE-BINDING FACTOR ACUTE MYELOID LEUKEMIA TREATED WITH FLUDARABINE, CYTARABINE, G-CSF (FLAG) BASED REGIMEN
Authors: T. Abuasab, J. Senapati, T. Kadia, F. Ravandi, C. DiNardo, N. Pemmaraju, M. Ohanion, Y. Alvarado, H. Kantarjian, G. Borthakur
Journal: HemaSphere (2022)

Background: Core-binding factor acute myeloid leukemia (CBF-AML), including inv (16) and t (8;21) AML, represent 15%-20% of all adult AML patients (pts) and is generally recognized as favorable AML subgroups. Despite being favorable, up to 30-50% of patients with CBF-AML eventually relapse. Both RAS (particularly multiclonal) and KIT mutations in CBF-AML have been associated with poor outcomes, but our initial analysis for patients treated with a fludarabine-based regimen did not support a negative impact of these mutations. In addition, we showed that the optimal reduction of disease defining transcripts (RUNX1-RUNX1T1 and CBFB-MYH11) by PCR at end of induction and end of consolidations, has the most impact on the relapse free survival of these patients. Aims: We studied the prognostic impact, in a consecutive cohort of CBF-AML patients treated uniformly, of kinase mutations (RAS and KIT) and the number (Single vs. multiple) of mutations in addition to the impact of mutation status on attainment of optimal PCR reductions at most informative pre-defined time points; end of induction and end of treatment. Methods: Pts aged ≥ 18 years (yrs) with de novo CBF-AML, treated with FLAG based regimen with idarubicin or gemtuzumab ozogamicin between April 2013 and December 2019 at our center were included in this analysis. RAS and KIT mutations were tested by next generation sequencing. PCR for disease-specific transcripts was monitored at the end of C1 and end of therapy (EOT). Optimal response was considered as PCR transcripts < 0.1% post C1 and <0.01% at EOT. Results: A total of 91 pts with CBF AML were evaluated with a median age of 52 yrs (range, 22-79), 41 of whom were females (45%). Fifty-three pts (58%) had Inv 16 and the rest had t (8;21). Twenty-six pts (29%) had FLT3 mutation (ITD and/or TKD), 32 pts (35%) had RAS mutation (19 pts with NRAS, 3 pts with KRAS, and 10 pts with both mutation), and 30 pts (33%) had KIT mutation. Out of 32 pts with RAS mutation, 16 (50%) had single mutation and16 (50%) had multiple RAS mutations, while of 30 pts with KIT mutation, 25 pts (83%) had single KIT mutation, and 5 pts (17%) had multiple KIT mutations. On regression analysis of presence of KIT or RAS mutation and their impact on end of induction and end of treatment PCR, only KIT mutation was associated with lower odds (0.33, 95% CI 0.11-0.9) of optimal EOT response. Amongst mutated pts, the presence of single versus multiple KIT or RAS mutation did not affect optimal PCR responses. At a median follow up of 53.1 months (mos), the median relapse free survival (RFS) for the whole cohort was 27.7 mos (range,1.7-93.6). RAS mutated pts had longer RFS compared to non-mutated pts (not reached vs. 43.78 mos, p=0.02); however, KIT mutation did not affect RFS. In addition, the number of the RAS or KIT mutation (One mutation vs. multiple mutations) also did not impact RFS. Image:Summary/Conclusion: KIT mutation might negatively affect attainment of optimal PCR responses at end of FLAG based therapy, but it lacked significant impact on relapse free survival. Single versus multiple KIT or RAS mutations also do not seem to have an impact on therapy response.